The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission

Ruben K Dagda; Ronald A Merrill; J Thomas Cribbs; Yucui Chen; Johannes W Hell; Yuriy M Usachev; Stefan Strack

doi:10.1074/jbc.M800989200

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The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission

Journal article

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Peer reviewed

The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission

Ruben K Dagda, Ronald A Merrill, J Thomas Cribbs, Yucui Chen, Johannes W Hell, Yuriy M Usachev and Stefan Strack

The Journal of biological chemistry, Vol.283(52), pp.36241-36248

12/26/2008

DOI: 10.1074/jbc.M800989200

PMCID: PMC2605997

PMID: 18940801

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Abstract

The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bbeta1 and Bbeta2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bbeta2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bbeta2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bbeta2 expression induces mitochondrial fragmentation, whereas Bbeta2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.

Carrier Proteins - physiology

Protein Phosphatase 2 - physiology

Cell Survival

Carrier Proteins - biosynthesis

Protein Phosphatase 2 - genetics

Rats

Mitochondria - metabolism

PC12 Cells

Hippocampus - metabolism

Animals

Ischemia

Epistasis, Genetic

Models, Biological

Protein Phosphatase 2 - metabolism

Rotenone - pharmacology

Neurons - metabolism

Apoptosis

RNA - metabolism

Spinocerebellar Ataxias - genetics

Details

Title: Subtitle: The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission
Creators: Ruben K Dagda - Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USA
Ronald A Merrill
J Thomas Cribbs
Yucui Chen
Johannes W Hell
Yuriy M Usachev
Stefan Strack
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.283(52), pp.36241-36248
DOI: 10.1074/jbc.M800989200
PMID: 18940801
PMCID: PMC2605997
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: NS054614 / NINDS NIH HHS F31 NS049659 / NINDS NIH HHS NS043254 / NINDS NIH HHS R01 NS035563 / NINDS NIH HHS R01 NS046450 / NINDS NIH HHS NS056244 / NINDS NIH HHS NS046450 / NINDS NIH HHS
Language: English
Date published: 12/26/2008
Academic Unit: Pathology; Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology; Ophthalmology and Visual Sciences
Record Identifier: 9984040222202771

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